The present invention relates to bis-aryl carbinol derivatives, pharmaceutical compositions and methods of using such derivatives.
International Publication Number WO 89/10369 discloses compounds of the formula: ##STR2## wherein: one of a, b, c and d represents nitrogen or --NR.sup.11 --, wherein R.sup.11 is, amongst others, O.sup.-, and the remaining a, b, c and d groups are CH; T represents carbon or nitrogen, with the dotted line attached to T representing an optional double bond when T is carbon; when m plus n equals 1 or 2, X represents, amongst others, --O-- or --S(O).sub.e -- wherein e is 0, 1 or 2; when m plus n represents 0, X can be, amongst others, any substituent for m plus n equalling 1, a direct bond or propenylene; when m plus n equals 3 then X equals a direct bond; each R.sup.a may be, amongst others, H; Z represents .dbd.O or .dbd.S such that when Z is O, R may be, amongst others, ##STR3## wherein Y is N or NR.sup.11 ; when Z represents .dbd.S, R represents in addition to the R group above, aryloxy or alkoxy.
WO 89/10369 generically discloses compounds which can have the structure: ##STR4## wherein Z can be O and R can be: ##STR5## wherein Y can be NR.sup.11 and R.sup.11 can be --O.sup.- ; however, no specific compounds are disclosed with this structure.
U.S. Pat. No. 4,826,853 issued to Piwinski et al. on May 2, 1989 is the priority document for WO 88/03138 which published on May 5, 1988. WO 88/03138 discloses compounds of the formula ##STR6## wherein: one of a, b, c and d represents N or NR.sup.9 where R.sup.9 is, amongst others, O, and the remaining a, b, c and d groups are CH; X represents N or C, which C may contain an optional double bond to carbon atom 11; Z represents O, S or H.sub.2 such that when Z is O, R may be, amongst others, ##STR7## when Z represents S, R represents in addition to the R group above, aryloxy or alkoxy; and when Z represents H.sub.2, R can be, amongst others, ##STR8## These compounds are disclosed as being useful in the treatment of allergy and inflammation.
In particular, WO88/03138 discloses intermediates having the formulas: ##STR9##
During the course of research on the compounds disclosed in WO 88/03138, it was generally found that the compounds having a carbonyl group (Z=O) attached to the piperidyl, piperidylidenyl or piperazinyl nitrogen atom were much stronger antagonists of platelet activating factor (PAF) than the compounds having a CH.sub.2 group (Z=H.sub.2) attached thereto.
WO 90/13548 published on Nov. 15, 1990 on PCT/US90/02251 which was filed on Apr. 30, 1990 and claims priority to U.S. application Ser. No. 345,604 filed May 1, 1989 discloses compounds similar in structure to the compounds disclosed in WO 88/03138 with the difference being that the R group represents an N-oxide heterocyclic group of the formula (i), (ii), (iii), or (iv): ##STR10## wherein R.sup.9, R.sup.10, and R.sup.11 can be, amongst other groups, H.
European Patent Application, Publication No. 0 371 805, published Jun. 6, 1990, priority based on Japanese 303461/88 (30 Nov. 1988) and JP64059/89 (16 Mar. 1989) discloses compounds useful as hypotensives having the formula: ##STR11## wherein: X represents an aralkyl- or aryl-containing group having from 6 to 30 carbon atoms; Y represents a heteroatom or an optionally substituted alkylene chain, the alkylene chain optionally containing hetero atom(s) or unsaturated bond(s); and A represents an optionally substituted condensed aromatic or heterocyclic ring. It is also disclosed that if present, the aromatic ring of X or A is benzene, pyridine, pyridazine, or pyrazine, amongst others. Amongst the specific compounds disclosed there is included: (1) 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-Picolyl)piperidine; (2) 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(3-Picolyl)piperidine; and (3) 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-Picolyl)piperidine. It is believed the structures of these compounds are: ##STR12##
Galantay et al., Journal of Medicinal Chemistry, 1974, Vol. 17, No. 12, pp. 1316 to 1327 discloses oxazole and thiazole analogs of amitriptyline. A disclosed intermediate has the formula: ##STR13##
U.S. Pat. No. 4,659,716 discloses an intermediate of the formula: ##STR14##
PCT/US89/01689, International Publication Number WO 89/10363, published Nov. 2, 1989, which generically discloses compounds of this invention, discloses compounds of the formula: ##STR15## wherein T represents .dbd.O or ##STR16## Q represents CH, N or N.fwdarw.O; ring A represents defined heterocyclic aromatic rings (see pp. 3 and 4 for example); U is --H or --OH when the bond between W and the cyclohepta ring is a single bond (see, for example, Compound 17 in Reaction f on page 17); W represents C, N or N.fwdarw.O and the dotted line drawn to W from the cyclohepta ring represents an optional double bond when W is C, or is absent when W is N.fwdarw.O; and X can be, amongst others: ##STR17## wherein Z is O or S; R.sup.1 can be, amongst others, H, alkyl, cycloalkyl, aryl, and heteroaryl (the definition of heteroatom includes N.fwdarw.O); and R.sup.x can be alkyl, aralkyl or aryl.